Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract Incidence and mortality from post-myocardial infarction (MI) heart failure (HF) are increasing and becoming a major health problem worldwide. There is an urgent need for novel therapy to minimize MI and promote post- MI wound healing. Acutely, interleukin-2 (IL-2) protects the myocardium against both ischemic and reperfusion injury (IRI), via interaction of its opioid binding domain with peripheral ?- and/or ???opioid receptors in adult cardiomyocytes. Chronically, administration of low-dose rIL-2 promotes cardiac wound healing through activation of high affinity receptor preferably inducing expansion of regulatory T cells (Tregs). In addition, treatment with low- dose rIL-2 halts the progression of atherosclerosis and stabilizes established atherosclerotic lesions in animal models. Importantly, MI and HF patients have a deficiency in Tregs frequency and function. Recent clinical trials demonstrate that low-dose rIL-2 therapy was well tolerated, preferentially enhanced Tregs, and improved clinical outcomes in patients with autoimmune or inflammatory diseases without causing immunosuppression. Thus, treatment with rIL-2 based therapy carries a high therapeutic potential to minimize infarct size, prevent HF development and recurrent MI, and improve clinical outcome. However, current low-dose rIL-2 therapy has a very short half-life and causes local reaction at injection sites, with an unwanted increase in several innate immune cell types such as natural killer cells and eosinophils. To obtain ideal outcomes in patients, we have designed a proprietary IL-2 analog that activates peripheral ?- and/or ???opioid receptors and enables selective stimulation of Tregs, while minimizing negative clinical effects. The specific aim of this Phase I SBIR proposal is to determine, using a murine model of HF induced with 90 min closed-chest IRI, whether acute or weekly treatment with a proprietary IL2 analog will effectively attenuate MI and prevent HF development for 28 days of follow-up. APT Confidential